DESCRIPTION: This revised continuation application proposes three specific aims designed to address the role of melatonin in the growth and physiology of human breast cancer: (1) to define the receptor pathway(s), membrane or nuclear, which mediate the growth-inhibitory and ER-modulatory effects of melatonin; (2) to begin to delineate the cellular pathways activated by melatonin and retinoic acid which induce apoptosis in MCF-7 cells; and (3) to move our studies of the apoptotic effects of melatonin and retinoic acid from the in vitro setting to a more physiologically relevant in vivo model system. By defining the role of melatonin in mammary tumorigenesis and its interaction with other hormone pathways, these studies will begin to define the determinants of hormone-responsiveness and hormone-unresponsiveness which are critical in the diagnosis, treatment, and prognosis of breast cancer and may ultimately provide important insight into the prevention of breast cancer.